title: Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cells enriched with tumor spheroids from a non-small cell lung cancer cell line.
abstract: Evaluating the effects of novel drugs on appropriate tumor models has become crucial for developing more effective therapies that target highly tumorigenic and drug-resistant cancer stem cell (CSC) populations. In this study, we demonstrate that a subset of cancer cells with CSC properties may be enriched into tumor spheroids under stem cell conditions from a non-small cell lung cancer cell line. Treating these CSC-like cells with gemcitabine alone and a combination of gemcitabine and the novel CHK1 inhibitor PF-00477736 revealed that PF-00477736 enhances the anti-proliferative effect of gemcitabine against both the parental and the CSC-like cell populations. However, the CSC-like cells exhibited resistance to gemcitabine-induced apoptosis. Collectively, the spheroid-forming CSC-like cells may serve as a model system for understanding the mechanism underlying the drug resistance of CSCs and for guiding the development of better therapies that can inhibit tumor growth and eradicate CSCs.
authors.affiliation: Oncology Research Unit, Pfizer, Inc., 10777 Science Center Drive, San Diego, CA, 92121, USA, douglasfang@yahoo.com.
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Fang
authors.forename: Joan
authors.initials: J
authors.lastname: Cao
authors.forename: Jitesh P
authors.initials: JP
authors.lastname: Jani
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Tsaparikos
authors.forename: Alessandra
authors.initials: A
authors.lastname: Blasina
authors.forename: Jill
authors.initials: J
authors.lastname: Kornmann
authors.forename: Maruja E
authors.initials: ME
authors.lastname: Lira
authors.forename: Jianying
authors.initials: J
authors.lastname: Wang
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Jirout
authors.forename: Justin
authors.initials: J
authors.lastname: Bingham
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhu
authors.forename: Yin
authors.initials: Y
authors.lastname: Gu
authors.forename: Gerrit
authors.initials: G
authors.lastname: Los
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Hostomsky
authors.forename: Todd
authors.initials: T
authors.lastname: Vanarsdale
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001570:Benzodiazepinones / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011720:Pyrazoles / Q000008:administration & dosage; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D014408:Biomarkers, Tumor; C532366:PF 00477736; D011720:Pyrazoles; D003841:Deoxycytidine; D000093542:Gemcitabine